Published online May 1, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. 1032-1033 (doi:10.1542/peds.2006-3669)
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LETTER TO THE EDITOR

Movement of Bilirubin and Bilirubin Conjugates Across the Placenta

Antony F. McDonagh, PhD
Divison of Gastroenterology
Department of Medicine
University of California
San Francisco, CA 94143

To the Editor.—

The recent report1 of a woman with conjugated hyperbilirubinemia who delivered an infant with negligible concentrations of bilirubin in serum at birth echoes an earlier report of a similar phenomenon. In 1973, Lipsitz et al2 described a pregnant patient with a total plasma bilirubin concentration of 24 mg% (13 mg% direct bilirubin) on the day of delivery and whose male infant showed a cord blood total bilirubin concentration of 10.4 mg%, of which only 0.6 mg% was direct-reacting bilirubin. These observations are consistent with experimental studies in rhesus monkeys that showed that conjugated bilirubin does not cross the placenta from the maternal to the fetal circulation.3 Investigations in the guinea pig and monkey also showed that bilirubin glucuronides do not cross the placenta in the reverse direction, from fetus to mother.3,4 Thus, bilirubin glucuronides do not cross the placenta readily in either direction in vivo.

In the patients noted above, the direct-reacting pigment in maternal plasma would have been a mixture containing both bilirubin glucuronides and isomers of these resulting from acyl migration of the glucuronic acid,5 all of which would give the diazo reaction for direct bilirubin. Therefore, not only bilirubin glucuronides but other glucuronic acid esters of bilirubin fail to cross the human placenta readily. Although the placenta contains membrane transport proteins that effect the efflux of bilirubin glucuronides from the liver,6–8 it would seem that these transporters do not facilitate placental passage of bilirubin glucuronides or their acyl-migrated isomers in either direction in pregnant women.

The observations of mothers with conjugated hyperbilirubinemia contrast markedly with observations of mothers with unconjugated hyperbilirubinemia, a situation that is seen in patients with Crigler-Najjar syndrome.9–11 Because of a congenital deficiency in bilirubin conjugation, these patients have lifelong unconjugated hyperbilirubinemia. Healthy newborns of mothers with Crigler-Najjar syndrome invariably have elevated plasma levels of unconjugated bilirubin at birth. Notably, the plasma concentrations of bilirubin observed in the newborns are roughly the same as those in the mother. For example, in a recent report, the total bilirubin concentration (all indirect) was 242 µM (14.2 mg%) in the mother at delivery, 247 µM (14.4 mg%) in the newborn, and 222 µM (13.0 mg%) in both the umbilical artery and vein.9 (Similarly, in mothers with marked elevations of both conjugated and unconjugated bilirubin fractions in plasma, the concentration of unconjugated bilirubin in neonatal blood has been found to be similar to that in the maternal circulation.2,12) These observations are consistent with experiments in the guinea pig and monkey, which have shown that unconjugated bilirubin, in contrast to bilirubin glucuronides, passes readily in both directions across the placenta.3,4,13 They challenge the notion that bilirubin does not readily cross from the maternal to the fetal circulation.6,14 Furthermore, the apparent close equivalence between maternal and neonatal (fetal) unconjugated bilirubin concentrations in humans strongly suggests that passive diffusion is the predominant mechanism for the bidirectional placental flux of bilirubin in these patients and that active transport14–16 is of little, if any, importance. It is possible, however, that under these pathologic conditions bilirubin saturates placental membrane transport protein(s), which under normal conditions might facilitate efflux of bilirubin from the fetal to the placental circulation.

REFERENCES

  1. Raimondi F, Capasso L, Migliaro F, Romano A, Paludetto R. Prenatal exposure to conjugated bilirubin. Pediatrics. 2006;118 :2265[Free Full Text]
  2. Lipsitz PJ, Flaxman LM, Tartow LR, Malek BK. Maternal hyperbilirubinemia and the newborn. Am J Dis Child. 1973;126 :525 –527[Medline]
  3. Bashore RA, Smith F, Schenker S. Placental transfer and disposition of bilirubin in the pregnant monkey. Am J Obstet Gynecol. 1969;103 :950 –958[ISI][Medline]
  4. Schenker S, Dawber NH, Schmid R. Bilirubin metabolism in the fetus. J Clin Invest. 1964;43 :32 –39[ISI][Medline]
  5. McDonagh AF, Lauff JJ, Wu TW, Palma LA. Origin of mammalian biliprotein and isomerization of bilirubin glucuronides in vivo. J Clin Invest. 1984;74 :763 –770[ISI][Medline]
  6. Marin JJ, Macias RI, Serrano MA. The hepatobiliary-like excretory function of the placenta: a review. Placenta. 2003;24 :431 –438[CrossRef][ISI][Medline]
  7. St-Pierre MV, Serrano MA, Macias RI, et al. Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol. 2000;279 :R1495 –R1503[Abstract/Free Full Text]
  8. Pascolo L, Fernetti C, Pirulli D, Crovella S, Amoroso A, Tiribelli C. Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochem Biophys Res Commun. 2003;303 :259 –265[CrossRef][ISI][Medline]
  9. Gajdos V, Petit F, Trioche P, et al. Successful pregnancy in a Crigler-Najjar type I patient treated by phototherapy and semimonthly albumin infusions. Gastroenterology. 2006;131 :921 –924[CrossRef][ISI][Medline]
  10. Holstein A, Plaschke A, Lohse P, Egberts EH. Successful photo- and phenobarbital therapy during pregnancy in a woman with Crigler-Najjar syndrome type II. Scand J Gastroenterol. 2005;40 :1124 –1126[CrossRef][ISI][Medline]
  11. Smith JF Jr, Baker JM. Crigler-Najjar disease in pregnancy. Obstet Gynecol. 1994;84 :670 –672[Medline]
  12. Waffarn F, Carlisle S, Pena I, Hodgman JE, Bonham D. Fetal exposure to maternal hyperbilirubinemia: neonatal course and outcome. Am J Dis Child. 1982;136 :416 –417[Abstract]
  13. McDonagh AF, Palma LA, Schmid R. Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig. Biochem J. 1981;194 :273 –282[ISI][Medline]
  14. Briz O, Macias RI, Serrano MA, Gonzalez-Gallego J, Bayon JE, Marin JJ. Excretion of foetal bilirubin by the rat placenta-maternal liver tandem. Placenta. 2003;24 :462 –472[CrossRef][ISI][Medline]
  15. Serrano MA, Bayon JE, Pascolo L, et al. Evidence for carrier-mediated transport of unconjugated bilirubin across plasma membrane vesicles from human placental trophoblast. Placenta. 2002;23 :527 –535[CrossRef][ISI][Medline]
  16. Pascolo L, Fernetti C, Garcia-Mediavilla MV, Ostrow JD, Tiribelli C. Mechanisms for the transport of unconjugated bilirubin in human trophoblastic BeWo cells. FEBS Lett. 2001;495 :94 –99[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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